Division of HIV/AIDS
National Center for Infectious Diseases
Centers for Disease Control and Prevention

Summary

Pneumocystis carinii pneumonia (PCP) is the most common
opportunistic
infection in children who have acquired immunodeficiency syndrome
(AIDS).
Despite the publication of guidelines for prophylaxis against PCP
for
children infected with human immunodeficiency virus (HIV) in 1991
(1),
ongoing AIDS surveillance has detected no substantial decrease in
PCP
incidence among HIV-infected infants. Studies indicate that this
continued
incidence is associated with failure to identify HIV-infected
children
before PCP occurs and with limitations in the ability of CD4+
measurements
to identify children at risk for PCP. In March 1994, the National
Pediatric
& Family HIV Resource Center, * in collaboration with CDC, convened
a
working group to review additional data about the occurrence of PCP
among
HIV-infected children and to reevaluate the 1991 PCP prophylaxis
guidelines
for children. This report summarizes these new data and presents
revised
PCP prevention guidelines that recommend a) promptly identifying
children
born to HIV-infected women and initiating regular diagnostic and
immunologic monitoring of such children; b) beginning PCP
prophylaxis at
4-6 weeks of age for all children who have been perinatally exposed
to HIV;
c) continuing prophylaxis through 12 months of age for HIV-infected
children; and d) making decisions regarding prophylaxis for
HIV-infected
children greater than or equal to 12 months of age based on CD4+
measurements and whether PCP previously has occurred.

INTRODUCTION

In 1991, guidelines for prophylaxis against Pneumocystis
carinii
pneumonia (PCP) for children infected with human immunodeficiency
virus
(HIV) were developed by a working group convened by the National
Pediatric
& Family HIV Resource Center (1). These guidelines addressed the
need for
prompt identification of infants born to HIV-infected women (i.e.,
HIV-exposed infants), measurement of such infants' CD4+
T-lymphocyte counts
(CD4+ counts) and percentage of total lymphocytes (CD4+ percentage)
first
upon identification and then serially thereafter, and initiation of
PCP
prophylaxis based on age-associated CD4+ measurement values. In
addition,
the guidelines recommended that all children who had had a previous
episode
of PCP be maintained on prophylaxis, regardless of their CD4+
measurement
values.

Since publication of these guidelines, additional data have
been
collected that address a) the specificity and sensitivity of CD4+
count
thresholds for indicating risk for PCP, b) changes in CD4+ counts
preceding
an episode of PCP, c) correlation of CD4+ counts with CD4+
percentages, d)
medications used for prophylaxis, and e) factors underlying the
continued
incidence of PCP among children. In March 1994, the National
Pediatric &
Family HIV Resource Center, in collaboration with CDC, convened a
working
group to review this new information and to reevaluate the 1991 PCP
prophylaxis guidelines for children. This report summarizes that
information and presents the group's recommendations for PCP
prophylaxis
for children less than 13 years of age.

BACKGROUND

Identification of Children at Risk for PCP

Among children with perinatally acquired HIV infection, PCP
occurs
most often in infants 3-6 months of age (2). PCP in infants (i.e.,
children
less than 12 months of age) is often acute in onset and results in
a poor
prognosis. Effective prevention of PCP among HIV-infected infants
requires
that exposure to HIV be identified either before or immediately
following
birth so that prophylaxis can be initiated before 2 months of age
(the age
at which the risk for PCP begins to increase dramatically) (2). The
recent
demonstration of the efficacy of zidovudine in lowering the rate of
perinatal HIV transmission emphasizes the importance of identifying
pregnant women with HIV infection as early as possible (3). Thus,
through
prenatal HIV counseling and voluntary testing, pregnant women who
are
infected with HIV can be offered interventions to a) maintain or
improve
their own health, b) reduce the risk for transmitting HIV infection
to
their children, and c) prevent PCP in their children if they also
become
infected.

At present, however, many HIV-exposed children are not
identified
early enough to be offered prophylaxis before the period of highest
risk
for PCP. Studies have indicated that only 35%-55% of HIV-exposed
children
have been identified by their health-care providers (4-6). A study
of
HIV-infected children diagnosed with PCP in the United States
during
1991-1993 indicated that 59% of the children who had not received
prophylaxis had not been identified as being at risk for HIV
infection soon
enough for prophylaxis to be initiated (7). Failure to identify and
evaluate pregnant women with HIV infection and HIV-exposed children
by
early infancy substantially limits the effectiveness of any PCP
prophylaxis
strategy in preventing PCP among HIV-infected children.

CD4+ Count and PCP Among HIV-Infected Children

Data available when the 1991 prophylaxis guidelines were
published
indicated that approximately 10% of children diagnosed with PCP at
less
than 12 months of age had CD4+ counts of greater than or equal to
1,500
cells/uL, the threshold for prophylaxis in this age group as
defined in the
1991 guidelines. Recently published data, however, suggest that
this
percentage may be even higher among HIV-infected infants diagnosed
with PCP
at less than or equal to 6 months of age, the age at which most
cases of
PCP occur (7-9). Moreover, CD4+ counts can drop rapidly in infants
during
the few months preceding PCP diagnosis. For example, in one study
of
children with PCP, 26% of children less than 6 months of age had
CD4+
counts of greater than or equal to 1,500 cells/uL at the time of
PCP
diagnosis (Table_1) (7). In the same study, among 129 infants
less than
1 year of age who had CD4+ counts measured before or at the time of
PCP
diagnosis, the estimated decline of CD4+ counts during the 3 months
preceding the PCP diagnosis was 967 cells/uL (95% confidence
interval=
724-1,210 cells/uL) (7). Because HIV-infected infants less than 1
year of
age are at risk for PCP even with CD4+ counts of greater than or
equal to
1,500 cells/uL and because these infants might have counts that
drop to
this level or lower between measurements, the usefulness of CD4+
counts in
determining the need for prophylaxis among infants in this age
group is
limited.

Few data are available regarding CD4+ counts at the time of
PCP
diagnosis for children greater than 1 year of age. In three
previously
published studies of children who had PCP, one (5%) of 18 children
1-5
years of age had a CD4+ count of greater than or equal to 500
cells/uL, and
two (22%) of nine children 6-12 years of age had counts of greater
than or
equal to 200 cells/uL (10-12). In a recent study, three (16%) of 19
children 1-5 years of age had CD4+ counts of greater than or equal
to 500
cells/uL at the time of PCP diagnosis; each of these three children
had
CD4+ counts that declined rapidly at approximately the time of PCP
diagnosis (Table_1) (7). Also, all seven of the children
greater than
or equal to 6 years of age who developed PCP had CD4+ counts of
less than
200 cells/uL (Table_1).

Correlation of CD4+ Counts with CD4+ Percentages

Measurements of CD4+ percentages may be subject to less
variation than
those of CD4+ counts (13); thus, some clinicians prefer using CD4+
percentage to monitor immunosuppression in HIV-infected children.
In the
1991 guidelines (1), the prophylaxis threshold of less than 20%
that had
been recommended previously for adolescents and adults (14) was
also
recommended for children. However, the potentially low sensitivity
of this
threshold for the risk for PCP among young children was recognized.
Recently revised recommendations for PCP prophylaxis among
adolescents and
adults no longer include CD4+ percentage as a criterion for
prophylaxis
(15).

Data correlating CD4+ counts and percentages among
HIV-infected
children have been collected since 1991. These data have been used
to
develop a revised classification system for HIV infection among
children
that utilizes both CD4+ counts and percentages to categorize
children by
their level of immunosuppression (16) (Table_2). Correlation of
these
measurements has also allowed for determination of a CD4+
percentage level
that is more indicative of severe immunosuppression in children.

Diagnosis of HIV Infection Among Children

HIV infection can be diagnosed among children greater than or
equal to
18 months of age by using standard HIV IgG antibody tests. However,
because
maternal IgG can be present in children less than 18 months of age,
standard HIV-IgG serologic assays cannot be used to diagnose HIV
infection
in this age group. Advances in the development of viral detection
assays,
however, have made diagnosing HIV infection possible in nearly all
infants
by 4-6 months of age (17). The sensitivity of HIV culture or
polymerase
chain reaction (PCR) among infants is less than or equal to 50%
during the
first week after birth, but increases to greater than 90% by age 3
months
and to nearly 100% by 6 months of age (17-20). The use of these
assays has
been recommended for HIV-exposed children who are greater than or
equal to
1 month of age (21) because results of these assays can be used to
diagnose
HIV infection among infants (16).

Both the standard p24 antigen-capture assay and the
immune-complex-
dissociated, p24 antigen-capture assay are highly specific and can
be used
to diagnose HIV infection among infants (16). The sensitivity of
the
standard p24 antigen-capture assay, however, is low (i.e., less
than 50%)
in all age groups and therefore cannot be used to exclude HIV
infection.
Modification of the p24 antigen-detection assay by pretreating
serum
samples to dissociate antigen-antibody complexes has increased the
sensitivity of this assay (21,22). However, because data concerning
the
sensitivity of this assay in early infancy are limited, use of this
assay
alone is not currently recommended to exclude HIV infection.

RECOMMENDATIONS

The revised guidelines for PCP prophylaxis for children who
are
infected with or perinatally exposed to HIV are based on similar
considerations as the 1991 guidelines, including the age
distribution of
PCP among children, the rapid onset of PCP (especially among
infants), the
high mortality rate associated with PCP, and data regarding CD4+
counts and
percentages among HIV-infected children. Based on these
considerations and
more recent data, the following guidelines are recommended for PCP
prophylaxis among children less than 13 years of age.

Identifying Infants at Risk for HIV Infection

Infants born to HIV-infected women should be identified
promptly so
that prophylaxis can be initiated before these infants are at
risk for
PCP. Diagnosing HIV infection among women before or during
pregnancy
is the most beneficial way to accomplish this goal. Early
diagnosis
not only allows for prompt evaluation of the need for PCP
prophylaxis
among the infants of HIV-infected women, but also gives such
women the
opportunity to access interventions that could a) maintain or
improve
their own health status and b) reduce the risk for
transmitting HIV
infection to their children (e.g., through antiretroviral
therapy and
avoidance of breastfeeding).

If maternal HIV infection is not identified prenatally,
pediatric
health-care providers should identify infants born to
HIV-infected
women as soon as possible after birth so that PCP prophylaxis
can
begin promptly. Availability of and access to health care for
both
HIV-infected women and their newborns are essential to the
implementation of an effective PCP prophylaxis strategy.

Diagnostic and Immunologic Monitoring of HIV-Exposed Infants

All infants born to HIV-infected women should be monitored to
determine their HIV infection status; the use of HIV culture
or PCR is
the preferred method for diagnosing HIV infection among
infants (21).
These assays should be performed at least twice: once at less
than or
equal to 1 month of age and once at less than or equal to 4
months of
age. If the result of any test is positive, testing should be
repeated
to confirm diagnosis of HIV infection.

Although the use of CD4+ counts and percentages is no longer
recommended for determining the need for PCP prophylaxis among
HIV-exposed infants less than 1 year of age (see Initiating
PCP
Prophylaxis Among HIV-Exposed Infants), other clinical
considerations
for such infants rely on these measurements. These include the
assessment of such infants' immune status, risk for disease
progression, and need for continued PCP prophylaxis after 1
year of
age (see PCP Prophylaxis for HIV-Infected Children less than
or equal
to 12 Months of Age). Therefore, CD4+ counts and percentages
should be
measured in all HIV-exposed infants at 1 and 3 months of age
(Table_3). CD4+ monitoring is not necessary after HIV
infection
has been reasonably excluded (see PCP Prophylaxis for Infants
4-12
Months of Age). For infants who have been diagnosed as
HIV-infected
and for those whose infection status has not yet been
determined, CD4+
values should be monitored at 6, 9, and 12 months of age.

Initiating PCP Prophylaxis Among HIV-Exposed Infants

All infants born to HIV-infected women should be started on
PCP
prophylaxis at 4-6 weeks of age, regardless of their CD4+
count
(Table_3). Infants who are first identified as being
HIV-exposed
after 6 weeks of age should be started on prophylaxis at the
time of
identification. These recommendations are based on the
following
considerations: a) most cases of PCP among HIV-infected
children occur
in the first year of life; b) the risk for PCP begins to
increase
dramatically at age 2 months (when HIV infection cannot yet be
reasonably excluded) (see PCP Prophylaxis For Infants 4-12
Months of
Age); and c) the reliability of CD4+ counts in predicting
which
infants are at risk for PCP is relatively low during infancy
particularly among infants less than or equal to 6 months of
age, the
age at which the peak incidence of PCP occurs.

PCP prophylaxis should not be administered to infants less
than 4
weeks of age because a) they are at low risk for PCP and b)
the use of
sulfa drugs among infants at this age is not advised because
of the
potential for adverse drug effects resulting from immature
bilirubin
metabolism. Additionally, the concurrent use of sulfa drugs
among
HIV-exposed infants who are receiving zidovudine during the
first 6
weeks of life to prevent perinatal HIV transmission could
potentially
exacerbate the anemia that some children receiving zidovudine
experience (3). Therefore, to avoid the potential for
additional
toxicity in such children, prophylaxis should be started at 6
weeks of
age, the age at which zidovudine is discontinued.

PCP Prophylaxis for Infants 4-12 Months of Age

All HIV-infected infants and infants whose infection status
has not
yet been determined should continue prophylaxis until 12
months of
age.

PCP prophylaxis should be discontinued among infants in whom
HIV
infection has been reasonably excluded on the basis of two or
more
negative viral diagnostic tests (i.e., HIV culture or PCR),
both of
which are performed at greater than or equal to 1 month of age
and one
of which is performed at greater than or equal to 4 months of
age. In
some clinical centers, these viral diagnostic tests are not
available.
For children who do not have access to such testing,
prophylaxis
should be continued until 12 months of age unless HIV
infection has
been excluded on the basis of two or more negative HIV-
antibody tests
performed at greater than or equal to 6 months of age (16).

PCP Prophylaxis for HIV-Infected Children greater than or equal to
12
Months of Age

All HIV-infected children greater than or equal to 12 months
of age
should continue to have regular CD4+ monitoring to determine
their
need for PCP prophylaxis (Table_3).

HIV-infected children and children whose infection status has
not been
determined should be evaluated at 12 months of age to
determine their
need for continued PCP prophylaxis.

PCP prophylaxis should be continued after 12 months of age for
HIV-infected children who have had any CD4+ measurement during
the
first 12 months of life indicating severe immunosuppression
(i.e., a
CD4+ count of less than 750 cells/uL or a CD4+ percentage of
less than
15%). Prophylaxis should be discontinued at 12 months of age
for
HIV-infected children whose CD4+ measurements have been
adequately
monitored (Table_3) and have remained higher than these
levels.
PCP prophylaxis should also be discontinued for any child who
is
diagnosed as not being infected with HIV (16).

Children who have received PCP prophylaxis from 12 to 24
months of age
should be evaluated again at 24 months of age, and prophylaxis
should
be continued for those children who have had any CD4+
measurement
indicating severe immunosuppression (i.e., a CD4+ count of
less than
500 cells/uL or a CD4+ percentage of less than 15%).
Prophylaxis
should be discontinued at 24 months of age for HIV-infected
children
whose CD4+ measurements have been adequately monitored
(Table_3)
and have remained higher than these levels.

HIV-infected children greater than or equal to 12 months of
age who
are not receiving prophylaxis (e.g., those children whose
infection
was not identified previously or whose PCP prophylaxis was
discontinued) should begin PCP prophylaxis if their CD4+
measurement
indicates severe immunosuppression (Table_2).

Initiation or continuation of prophylaxis should also be
considered on
a case-by-case basis for HIV-infected children greater than or
equal
to 12 months of age who might otherwise be at risk for PCP,
such as
children with rapidly declining CD4+ counts or percentages or
children
with severely symptomatic HIV disease (i.e., Category C
conditions
{16}).

Prophylaxis Against PCP Recurrence

HIV-infected children who have had an episode of PCP should
receive
lifelong PCP prophylaxis to prevent recurrence -- regardless
of CD4+
measurement or clinical status.

Recommended Chemoprophylaxis Regimens

The recommended PCP chemoprophylaxis regimen for children is
trimethoprim/ sulfamethoxazole(TMP-SMX) (Box 1 Table_B1).
When
initiating TMP-SMX prophylaxis, a baseline complete blood
count,
differential count, and platelet count should be obtained.
These
measurements should be repeated monthly while the child is
receiving
prophylaxis.

If TMP-SMX is not tolerated, alternative regimens should be
followed.
On the basis of recently compiled pharmacokinetics data, the
revised
recommended dosage of dapsone as an alternative regimen is 2
mg/kg/day. These data indicate that peak serum concentrations
for
children receiving chronic dosing of dapsone at 1 mg/kg/dose
average
1.84 ug/mL, compared with average peak concentrations of 4.65
ug/mL
for adults receiving the standard dose of 100 mg/day (23,24).
The
increased dose of dapsone is recommended so that peak
concentrations
will approach concentrations achieved at dosages recommended
for
adults (15).

PCP prophylaxis is an approved labeling indication by the U.S.
Food
and Drug Administration for oral TMP-SMX but not for the
various other
alternative regimens for PCP prophylaxis.

TMP-SMX has been shown to substantially reduce the risk for
PCP among
HIV-infected children (25). However, clinicians should be
aware that
some children have developed PCP despite the use of
recommended
prophylaxis (26).

Education and Counseling

Providing HIV counseling and voluntary testing to all pregnant
women
and providing comprehensive pediatric care for infants born to
HIV-infected women are likely to be the most effective steps
toward
preventing PCP in children. The U.S. Public Health Service is
recommending voluntary HIV counseling and testing of all
pregnant
women because of the prevention opportunities these services
provide
for women and their infants (27). For uninfected women, such
counseling is intended to initiate or reinforce HIV
risk-reduction
behavior. For infected women, knowledge of their HIV infection
status
allows for more informed reproductive decisions, opportunities
to
reduce the risk for perinatal HIV transmission, and early
diagnosis
and treatment for themselves and their HIV-exposed infants.
Early
identification of HIV-exposed infants also allows for
education of
parents or other caregivers regarding treatment
considerations,
including PCP prophylaxis.

An optimal PCP prophylaxis strategy requires consistent
adherence to
the chemoprophylaxis regimen by the child's parent or other
caregiver.
Such adherence is likely to be enhanced if the caregiver is
knowledgeable about PCP and its prevention. Therefore, parents
and
other caregivers of HIV-exposed children should be provided
information that addresses

how HIV infection is diagnosed among infants, including
types and
sensitivities of available tests;

the relatively high risk for PCP among young infants;

the frequently sudden onset and high mortality of PCP
among
infants;

drug regimens for PCP chemoprophylaxis, including
efficacy and
the frequency and nature of potential adverse effects;

the importance of starting prophylaxis in all HIV-exposed
infants
at 4-6 weeks of age, even when the diagnosis of HIV
infection has
not been established; and

the rationale for having different prophylaxis strategies
for
adults and children.

Additionally, health-care providers should review the various
acceptable alternative dosing schedules with the child's
caregiver and
make every effort to tailor the dosing regimen to fit the
caregiver's
schedule.

FUTURE NEEDS

These recommendations were developed on the basis of currently
available data. Other strategies for prophylaxis might need to be
considered in the future. Factors that might influence the need to
modify
these guidelines include the extent to which a) the incidence of
PCP
decreases following implementation of these recommendations and
those for
HIV counseling and testing of pregnant women; b) improvements in
the
sensitivity and availability of HIV diagnostic tests allow for
diagnosis
and exclusion of HIV infection in most HIV-exposed infants before
the age
of greatest risk for PCP; and c) reduction in mother-to-infant HIV
transmission through zidovudine therapy results in an increased
number of
HIV-exposed but uninfected infants receiving PCP prophylaxis.

Thea DM, Lambert G, Weedon J, et al. Benefit of primary
prophylaxis
prior to 18 months of age in reducing the incidence of
Pneumocystis
carinii pneumonia and early death in a cohort of 112
HIV-infected
infants. Pediatrics 1995 (in press).

CDC. Availability of draft U.S. Public Health Service
recommendations
for HIV counseling and testing for pregnant women. Federal
Register
1995;60(36):10086-7.

Until September 1994, this organization was named the National
Pediatric
HIV Resource Center.

Table_1Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size.

TABLE 1. Number of children * with definitively diagnosed Pneumocystis carinii
pneumonia (PCP), by age at PCP diagnosis and CD4+ T-lymphocyte count +&
=================================================================================================
Age (mos) at PCP diagnosis
CD4+ T-lymphocyte ----------------------------------------
count (cells/uL) 0-5 6-11 12-23 24-71 >=72
---------------------------------------------------------------
>=1,500 22 0 1 @ 0 0
750-1,499 22 5 1 ** 0 0
500-749 8 4 0 1 ++ 0
200-499 13 6 2 3 0
<200 21 5 3 8 7
Total 86 20 7 12 7
---------------------------------------------------------------
* Numbers in italics refer to children with CD4+ T-lymphocyte counts that exceed the threshold
for prophylaxis in the 1991 guidelines (i.e., CD4+ counts of <1,500 cells/uL for children
1-11 months of age, <750 cells/uL for children ages 12-23 months, <500 cells/uL for
children 24 months to 5 years of age, and <200 cells/uL for children>=6 years of age).
+ Measurements were taken within 2 months of PCP diagnosis.
& CDC, unpublished data.
@ A child 12 months of age who had a CD4+ count of 1,662 cells/uL when first measured (at
the time of PCP diagnosis) and a CD4+ count of 832 cells/uL 3 months later.
** A child 18 months of age who had a CD4+ count of 1,010 cells/uL at the time of PCP
diagnosis, preceded 5 months earlier (which was the most recent measurement) by a CD4+
count of 3,120 cells/uL.
++ A child 30 months of age who had a CD4+ count of 530 cells/uL at the time of PCP diagnosis,
preceded 21 months earlier (which was the most recent measurement) by a CD4+ count of
3,514 cells/uL.
=================================================================================================

Table_3Note: To print large tables and graphs users may have to change their printer settings to landscape and use a small font size.

TABLE 3. Recommendations for PCP prophylaxis and CD4+ monitoring for human
immunodeficiency virus (HIV)-exposed infants and HIV-infected children, by age and
HIV-infection status
====================================================================================================
Age/HIV-infection status PCP prophylaxis CD4+ monitoring
------------------------------------------------------------------------------------------
Birth to 4-6 wks, HIV exposed No prophylaxis 1 month
4-6 wks to 4 mos, HIV exposed Prophylaxis 3 mos
4-12 mos
HIV infected or indeterminate Prophylaxis 6, 9, and 12 mos
HIV infection reasonably No prophylaxis None
excluded *
1-5 yrs, HIV infected Prophylaxis if: Every 3-4 mos +
CD4+ count is <500 cells/uL or
CD4+ percentage is <15% &@
6-12 yrs, HIV infected Prophylaxis if: Every 3-4 mos +
CD4+ count is <200 cells/uL or
CD4+ percentage is <15% @
------------------------------------------------------------------------------------------
* HIV infection can be reasonably excluded among children who have had two or more negative
HIV diagnostic tests (i.e., HIV culture or PCR), both of which are performed at >=1 month of age
and one of which is performed at >=4 months of age, or two or more negative HIV IgG antibody
tests performed at >6 months of age among children who have no clinical evidence of HIV
disease.
+ More frequent monitoring (e.g., monthly) is recommended for children whose CD4+ counts
or percentages are approaching the threshold at which prophylaxis is recommended.
& Children 1-2 years of age who were receiving PCP prophylaxis and had a CD4+ count of
<750 cells/uL or percentage of <15% at <12 months of age should continue prophylaxis.
@ Prophylaxis should be considered on a case-by-case basis for children who might otherwise
be at risk for PCP, such as children with rapidly declining CD4+ counts or percentages or
children with Category C conditions (16). Children who have had PCP should receive lifelong
PCP prophylaxis.
====================================================================================================

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